Our long-term goal is to understand the role of neuregulin1 (NRG1) and its receptor ErbB4 in neurotransmission, allowing for an improved understanding of their contribution to pathophysiology of schizophrenia. Both NRG1 and ErbB4 are susceptibility genes of this heritable and highly debilitating mental disorder that affects 1% of the general population. However, the biological basis of the increased risk with NRG1 and ErbB4 genes remains unclear. Recently, we demonstrated that NRG1 facilitates depolarization-induced GABA release in the prefrontal cortex (PFC) in a manner dependent on ErbB4, identifying a novel function of NRG1 } regulation of GABAergic transmission. While these preliminary observations are interesting and may provide insight into potential mechanisms by which the NRG1/ErbB4 signaling regulates pathogenesis of schizophrenia, more experiments are necessary to understand the role of NRG1 in the PFC. To this end, we proposed the following experiments. First, we will determine whether NRG1/ErbB4 regulates parvalbumin (PV)-positive GABAergic interneurons in the PFC. We will determine whether ErbB4 is expressed at terminals of PV-positive interneurons in the PFC and investigate whether NRG1 regulation of GABA release requires ErbB4 in PV-positive cells. Second, we will investigate mechanisms of NRG1/ErbB4 regulation of evoked GABA release. We will determine whether NRG1 regulation of evoked GABA release requires PI3 kinase, study if CYT-1 is able to rescue the phenotype in ErbB4 mutant slices, and investigate whether synapsin is a PI3 kinase- downstream target. Third, we will explore functions and underlying mechanisms of NRG1 regulation of evoked GABA release. We will determine whether the effect of NRG1 on pyramidal neuron activity require ErbB4 and PI3 kinase, characterize the effect of NRG1 on pyramidal neuron excitability, and investigate whether working memory are deficient in ErbB4 mutant mice. It is our hope that the proposed experiments will provide new insights into functions and underlying mechanisms of NRG1 in regulating activity- dependent GABA release. The results will likely to contribute to a better understanding of how this trophic factor and its receptor ErbB4 regulate pathogenesis of schizophrenia. PUBLIC HEALTH RELEVANCE: Our long-term goal is to understand the role of neuregulin1 (NRG1) and its receptor ErbB4 in pathophysiology of schizophrenia. This project is to investigate the novel functions of NRG1 and their underlying mechanisms. These studies will insight into potential mechanisms by which this trophic factor regulates synaptic plasticity. Such knowledge will contribute to a better understanding of pathogenesis of schizophrenia.